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  • Development of pyrazolopyrimidine based macrocyclic kinase inhibitors targeting AAK1
    by Mensing, T. E., Kurz, C. G., Amrhein, J. A., Ehret, T. A. L., Preuss, F., Mathea, S., Karim, M., Tran, D. H. N., Kadlecova, Z., Tolvanen, T., Martinez-Molina, D., Mueller, S., Einav, S., Knapp, S., Hanke, T.
    Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, has increased as an interesting strategy for the development of antiviral agents, as these agents may be effective against several different pathogens. NAK kinases is one such potential target family because they are involved in a variety of cellular functions, hijacked by viruses […]
  • Coordinated IFN-γ/TNF Axis Drives Selective Loss of Activated Enteric Glia in Inflammatory Bowel Diseases
    by Bubeck, M., Penkert, K. A., Limberger, H., Gonzalez Acera, M., Plattner, C., Ziegler, S., Muppirala, A. N., Forster, P., Jakob, M., Gamez-Belmonte, R., Erkert, L., Kulkarni, S., Guenther, C., Atreya, R., Kuehl, A. A., Hegazy, A., Hildner, K., Trajanoski, Z., Siegmund, B., Neurath, M. F., IBDome Consortium,, Rao, M., Progatzky, F. a., Lie, D. C., Becker, C., Romagnani, C., Ludwig, L. S., Klose, C. S. N., Patankar, J. V.
    Background: Enteric glial cells (EGC) play a crucial role in maintaining gut homeostasis, but their dysregulation in inflammatory bowel diseases (IBD) remains poorly understood. Emerging preclinical data suggests activated EGC have beneficial roles in controlling gut pathophysiology. Objective: Understanding EGC activation and adaptation during experimental and clinical IBD. Design: We provide the first highly integrated approach to identify EGC activation signature in IBD. Profiling 390 samples from IBD patients via bulk and single-nucleus (sn) transcriptomics and replicate the findings on […]
  • Identifying potential biomarkers of response to CCR5Δ32 HSCT in HIV infection
    by Chang, J., Gabhann, F. M.
    While HIV can be effectively suppressed to a chronic, mostly asymptomatic infection with combination antiretroviral therapy (cART), a cure is still needed. Hematopoietic stem cell transplantation (HSCT) from HIV-resistant donors has shown promise and has resulted in HIV remission in five patients. However, this treatment strategy does not guarantee HIV remission; six other patients who received a similar transplant had poor outcomes and died within a year of treatment. These different outcomes may be due to inter-individual differences in HIV […]
  • A slow and clathrin-dependent mode of compensatory endocytosis in hippocampal boutons at near-physiological temperature
    by Klingauf, J., Kahms, M., Pandey, S.
    The mode of presynaptic compensatory endocytosis has been controversial for decades. Recently, an ultrastructural study on synaptic membrane retrieval following synaptic vesicle fusion revealed an ultrafast mechanism of endocytosis in mouse hippocampal synapses at physiological temperature. Using live cell imaging of single-vesicle exo- and endocytosis in mouse hippocampal synapses, combined with accelerated optogenetic acidification of synaptic vesicles, we found that compensatory endocytosis occurs mostly through a slow clathrin-dependent and actin-independent mode at both room and physiological temperatures.
  • Metabolic Alteration in Oxylipins and Endocannabinoids Point to an Important Role for Soluble Epoxide Hydrolase and Inflammation in Alzheimer's Disease – Finding from Alzheimer's Disease Neuroimaging Initiative.
    by Borkowski, K., Yin, C., Kindt, A., Liang, N., de Lange, E. C. M., Blach, C., Newman, J., Kaddurah-Daouk, R., Hankemeier, T., Alzheimer's Disease Metabolomics Consortium,, Alzheimer's Disease Neuroimaging Initiative
    Mounting evidence implicates inflammation as a key factor in Alzheimer's disease (AD) development. We previously identified pro-inflammatory soluble epoxide hydrolase (sEH) metabolites to be elevated in plasma and CSF of AD patients and to be associated with lower cognition in non-AD subjects. Soluble epoxide hydrolase is a key enzyme converting anti-inflammatory epoxy fatty acids to pro-inflammatory diols, reported to be elevated in multiple cardiometabolic disorders. Here we analyzed over 700 fasting plasma samples from the baseline of Alzheimer's Disease Neuroimaging […]
  • TRUHiC: A TRansformer-embedded U-2 Net to enhance Hi-C data for 3D chromatin structure characterization
    by Li, C., Mowlaei, M. E., Human Genome Structural Variation Consortium,, HGSVC Functional Analysis Working Group,, Carnevale, V., Kumar, S., Shi, X.
    High-throughput chromosome conformation capture sequencing (Hi-C) is a key technology for studying the three-dimensional (3D) structure of genomes and chromatin folding. Hi-C data reveals important patterns of genome organization such as topologically associating domains (TADs) and chromatin loops with critical roles in transcriptional regulation and disease etiology and progression. However, the relatively low resolution of existing Hi-C data often hinders robust and reliable inference of 3D structures. Hence, we propose TRUHiC, a new computational method that leverages recent state-of-the-art deep […]
  • A Novel Aptamer-Based Approach for Lipoprotein Removal to Achieve Ultra-Pure Blood EV Isolation
    by Jeon, S., Kim, Y., SHIN, S.
    Blood extracellular vesicles (EVs) are nanoscale lipid-bilayer particles that carry proteins, nucleic acids, and metabolites, rendering them powerful tools for non-invasive liquid biopsy and targeted drug delivery. However, clinical translation of blood-derived EVs is severely limited by the co-isolation of lipoproteins, whose size (30 – 100nm) and density overlap with EVs, resulting in contaminated preparations that compromise biomarker accuracy and jeopardize therapeutic safety, efficacy, and biodistribution. To overcome this critical bottleneck, we developed ApoFilter, an aptamer-based affinity filtration platform engineered […]
  • Cationic amino acid identity and net charge influence condensate properties in E. coli
    by Kidane, A. K., Rosenfeld, J. R., Johnston, J. D., Dubbeldam, C., Paraan, M., Obermeyer, A. C.
    Understanding the formation of biomolecular condensates in biological systems has proven to be a paradigm shift in our understanding of the subcellular organization of biomacromolecules. From RNA metabolism, stress response mechanisms, and amyloidogenic pathologies, condensates have been implicated to play a role in a myriad of cellular phenomena. Despite their near ubiquity, we still do no wholly understand how the primary sequence of biomolecules influences their biophysical and rheological properties. Here, we aim to understand the impact of primary cationic […]
  • SpaceBF: Spatial coexpression analysis using Bayesian Fused approaches in spatial omics datasets
    by Seal, S., Neelon, B.
    Advancements in spatial omics technologies have enabled the measurement of expression profiles of different molecules, such as genes (using spatial transcriptomics), and peptides, lipids, or N-glycans (using mass spectrometry imaging), across thousands of spatial locations within a tissue. While identifying molecules with spatially variable expression is a well-studied statistical problem, robust methodologies for detecting spatially varying co-expression between molecule pairs remain limited. To address this gap, we introduce a Bayesian fused modeling framework for estimating molecular co-expression at both local […]
  • DNA Specimen Preservation using DESS and DNA Extraction in Museum Collections: A Case Study Report
    by Ogiso-Tanaka, E., Shimada, D., Ogawa, A., Ishiyama, G., Okumura, K.-i., Hosaka, K., Ishii, C., Nam, K. O., Hoshino, M., Nomura, S., Kakizoe, S., Nakamura, Y., Nishiumi, I., Ito, M. A., Kitayama, T., Tanaka, N., Hosoya, T., Jinbo, U.
    Recent advances in DNA research have increased the necessity for museums to preserve not only morphological specimens but also their DNA, leading us to maintain tissue samples linked to specimens at -80{degrees}C. DNA analysis has become an essential tool for taxonomic research and biodiversity assessment; however, freezer storage for all samples is impractical due to space limitations and operational costs. This creates a pressing need to develop more widely applicable DNA preservation methods. We investigated the comparative effects of traditional […]
  • Optically driven control of mechanochemistry and fusion dynamics of biomolecular condensates via thymine dimerization
    by Sheikhhassani, V., Wong, F. F. H. K., Bonn, D., Schmit, J. D., Mashaghi, A.
    Phase-separated biomolecular condensates serve as functional elements of biological cells, as contributors to the formation of protocells in prebiotic systems during early life, and as a distinct form of material with a range of applications. Regulation of condensate mechanochemistry is of critical importance for their functions and properties. Photochemical processes, such as UV-induced chemical changes, are commonly observed in nature and can have both detrimental and constructive impacts on life, and are also readily implemented in engineering applications. However, how […]
  • Brainwide genetic capture for conscious state transitions
    by Lazaro, H., Schneider, K. N., Jin, M., Beck, A., Rijsketic, D. R., Murry, A. D., Navarrete, J., Shin, C. C., Barrow, A. C., Campuzano, I., Nota, M. H., Ressler, N., Apley, E., Zhang, J., Gutierrez, G., Szelenyi, E. R., Nilsson, S. R., Denny, C. A., Bruchas, M. R., Heifets, B. D., de la Iglesia, H. O., Golden, S. A., Heshmati, M.
    Spatially integrated mechanisms of consciousness are unclear. An approach to manipulate brainwide circuits regulating consciousness via synthetic central nervous system activation may pave the way for more precise transitions in consciousness and reveal underlying mechanisms. Toward this goal, we leverage anesthesia as a tool to probe consciousness at cellular resolution within the intact network. We perform brainwide chemogenetic capture of isoflurane anesthesia-activated circuitry in mice in parallel with electrocorticography, wireless mechano-acoustic recording of peripheral physiology, and behavioral classification, to describe […]
  • ABERRANT NEURAL ADAPTATION TO EXPECTED UNCERTAINTY IN ADULTS WITH AUTISM SPECTRUM DISORDER
    by Pultsina, K., Kozunova, G., Chernyshev, B., Prokofyev, A., Tretyakova, V., Novikov, A., Rytikova, A., Stroganova, T.
    The ability to adjust brain resources to manage expected uncertainty is hypothesized to be impaired in autism spectrum disorder (ASD), though the evidence remains limited. To investigate this, we studied 23 neurotypical (NT) and 23 high-functioning adults with ASD performing a probabilistic two-alternative value-based task while undergoing magnetoencephalography (MEG) and pupillometry. The task comprised five sequential blocks with stable reward probabilities (70%:30%), but varying stimulus pairs and reward values, enabling the assessment of behavioral and neural adaptation to expected uncertainty. […]
  • Distinct alpha-synuclein strains derived from Parkinson's disease patient tissues trigger differential inclusion pathology in a novel biosensor cell model
    by Raina, A., Wang, W., Gonzalez, J. C., Yan, X., Overstreet-Wadiche, L., Wadiche, J., Zhang, C.-L., Chen, S. G.
    Background: -Synuclein (Syn) can misfold and aggregate to form fibrillar {beta}-sheet-rich aggregates ("strains") that are phosphorylated (p-Syn) and deposited into intracellular inclusions in the brain, the pathological hallmark of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Previously, we reported that seed amplification assays such as real-time quaking-induced conversion (RT-QuIC) amplifies and detects Syn strains from the patient skin. However, whether skin-derived Syn strains induce disease-specific pathological features in a biological system is […]
  • Targeting therapeutic nanoparticles to the glioblastoma resection margin by harnessing post-operative spatiotemporal blood-brain barrier disruption
    by Fernandes, L. F., Peeyatu, C., Dickie, B. R., Ho, Y. S., Thompson, L. A., Hernandez, N., Lozano, N., Kostarelos, K., Kisby, T.
    Resection surgery is the first-line therapy for glioblastoma (GBM) that is performed in >70% of patients, typically within days of suspected diagnosis. Current protocols for follow-on chemoradiotherapy have shown only modest efficacy in eliminating residual disease, leading to inevitable tumour recurrence. There remains a need for new approaches to swiftly and effectively treat post-operative residual disease to prevent the rapid early progression of recurrent GBM. Using syngeneic preclinical models of glioblastoma resection, we identified a spatially and temporally restricted window […]
  • Learning interpretable representation for context-specific transcription regulatory networks using a foundation model
    by Zhang, Y., Yu, Z., Yang, D., Chen, Q., Zhang, Y., Li, Z., Wang, Y., Wang, C.
    Gene expression is shaped by transcription regulatory networks (TRNs), where transcription regulators interact within regulatory elements in a context-specific manner. Despite significant efforts, understanding the intricate interactions of transcription regulators across different genomic regions and cell types remains a major challenge, largely due to data sparsity. Here, we introduce ChromBERT, a foundation model pre-trained on large-scale human ChIP-seq datasets. ChromBERT effectively captures the interaction syntax of approximately one thousand transcription regulators across diverse genomic contexts, generating interpretable representations of context-specific […]
  • Extending differential gene expression testing to handle genome aneuploidy in cancer
    by Davydzenka, K., Caravagna, G., Sanguinetti, G.
    Genome aneuploidy, characterized by Copy Number Variations (CNVs), profoundly alters gene expression in cancer. CNVs can directly influence transcription through gene dosage effects or indirectly through compensatory regulatory mechanisms. However, existing differential gene expression (DGE) testing methods do not differentiate between these mechanisms, conflating all expression changes and limiting biological interpretability. This misclassification can obscure key genes involved in tumor adaptation and progression, hindering biomarker discovery and leading to incomplete insights into cancer biology. To address this, we developed DeConveil, […]
  • Paired Analyses of Nuclear Protein Targets and Genomic DNA by Single-Cell Western Blot and Single-Cell PCR
    by Gomez Martinez, A. E., Lam, T., Herr, A.
    Single-cell multimodal assays measure multiple layers of molecular information. Existing single-cell tools have limited capability to analyze nuclear proteins and genomic DNA from the same originating single cell. To address this gap, we designed and developed a microfluidic single-cell assay (SplitBlot), that pairs measurements of genomic DNA (PCR-based) and nucleo-cytoplasmic proteins (nuclear histone H3 and cytoplasmic beta-actin). To accomplish this paired multiomic measurement, we utilize microfluidic precision to fractionate protein molecules (both nuclear and cytoplasmic) from genomic DNA (nuclear). We […]
  • Advancing EEG Biosensing: Novel Scalable Production of Platinum-Silicon Microneedles
    by Amir, M., Ding, R., Rusli, N. I., Vercooren, N., Ceyssens, F., Kuznetsova, N., Bertrand, A., Kraft, M., Taurino, I.
    This study presents the development and analysis of a silicon microneedle electrode array fabricated using a streamlined, two-step approach for enhanced bio-signal recording applications. Numerical simulations with COMSOL Multiphysics were employed to optimize the microneedle array design, focusing on mechanical stability and minimizing skin-electrode impedance. Structural analysis identified needle lengths between 500 m and 700 m as optimal for mechanical robustness, with critical load factors indicating a high resistance to buckling under applied forces. Optimal needle spacing was determined to […]
  • Estimating Brain Similarity Networks with Diffusion MRI
    by Sadikov, A., Choi, H., Cai, L. T., Mukherjee, P.
    Structural similarity has emerged as a promising tool in mapping the network organization of an individual, living human brain. Here, we propose diffusion similarity networks (DSNs), which employ rotationally invariant spherical harmonic features derived from diffusion magnetic resonance imaging (dMRI), to map gray matter structural organization. Compared to prior approaches, DSNs showed clearer laminar, cytoarchitectural, and micro-architectural organization; greater sensitivity to age, cognition, and sex; higher heritability in a large dataset of healthy young adults; and straightforward extension to non-cortical […]

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